In an aldol condensation reaction, an aldehyde or ketone, with a hydrogen atom alpha to the carbonyl, react together to form a β-hydroxy-aldehyde or a β-hydroxy-ketone. The β-hydroxy-aldehyde or β-hydroxy-ketone can dehydrate in the presence of either an acid or a base to give a conjugated α,β-unsaturated aldehyde or ketone. The conditions needed for the aldol dehydration are often only slightly more vigorous than the conditions needed for the aldol condensation itself. As a result, the product of such aldol reactions often comprises both the β-hydroxy aldehyde or ketone and the α,β-unsaturated aldehyde or ketone.
Many methods are known in the art for dehydrating β-hydroxy-aldehydes or β-hydroxy-ketones to α,β-unsaturated aldehydes or ketones in fair to excellent yields. These include simple heating; acid-catalyzed dehydration using mineral acids or solid acid catalysts, with or without azeotropic removal of the water of reaction, as exemplified in U.S. Pat. No. 5,583,263, U.S. Pat. No. 5,840,992, U.S. Pat. No. 5,300,654, and Kyrides, JACS, Vol 55, August, 1933, pp. 3431-3435; heating with iodine crystals as in Powell, JACS, Vol.46, 1924, pp. 2514-17; and base-catalyzed dehydration as taught in Streitwieser and Heathcock, “Introduction to Organic Chemistry”, 2nd Ed., 1981, pp. 392-396.
In some cases, it is desirable to selectively hydrogenate the carbon-carbon double bond of the α,β-unsaturated aldehyde or ketone to give a saturated aldehyde or ketone. Many catalysts and methods are known for such hydrogenation reactions, as exemplified in U.S. Pat. Nos. 5,583,263 and 5,840,992, and U.S. Pat. Publ. Nos., 2002/0128517, 2002/058846, and 2002/0169347. Commercially important products of this type include methyl isobutyl ketone, made by the self-condensation of acetone; and methyl amyl ketone, methyl isoamyl ketone, and methyl propyl ketone, made by the crossed condensation of acetone with n-butryaldehyde, isobutyraldehyde, and acetaldehyde, respectively.
In other cases it is desirable to hydrogenate the carbon-carbon double bond of the α,β-unsaturated aidehyde or ketone, as well as the carbonyl group, to give a saturated alcohol. Many catalysts and methods are known for such hydrogenation reactions, as exemplified in U.S. Pat. Nos. 2,088,015, 2,088,016, 2,088,017, and 2,088,018. Such alcohols are useful in the production of surfactants and esters.
Aldehydes are more reactive, in general, than are ketones in base-catalyzed aldol condensations because of the greater ease of enolate ion formation of an aldehyde. As such, in a crossed condensation of a ketone with an aldehyde to produce a desired β-hydroxyketone, the self-condensation of the aldehyde is expected to occur in substantial quantities to produce an undesired β-hydroxyaldehyde by-product. Further, unhindered aldehydes, i.e., straight-chain aldehydes such as acetaldehyde, propionaldehyde, n-butyraldehyde, and n-pentanal, are more reactive toward self-condensation than hindered aldehydes, i.e., branched aldehydes such as 2-methyl-propanal and 3-methyl-butanal.
It is understood that the rate-limiting step in these reactions is often enolate ion formation, and that condensation and the subsequent dehydration reaction occur in rapid succession. These α-β unsaturated ketones and aldehydes are known to those skilled in the art to be quite reactive and susceptible to further consecutive, non-selective condensation, cyclization, and Michael-type addition reactions with the starting ketones and aldehydes, as well as themselves and other ketonic and aldehydic by-products. See, for example, H.O. House, Modern Synthetic Reactions, 2nd. Ed., 1972 pp. 595-599, 629-640.
Thus, without being bound by any theory, in the base-catalyzed condensation of an aldehyde of Formula 1, possessing at least one hydrogen atom alpha to the carbonyl, with a ketone of Formula II, to form a desired β-hydroxy-ketone or α-β unsaturated ketone of Formulae III or IV, three parallel reaction pathways are known to compete: 
In general, R2 represents a C1 to C10 organic radical and R1, R3, and R4 represent hydrogen or a C1 to C10 organic radical.
R1 may represent a hydrogen, or else R1 and R2 may form members of a common cycloalkyl or aromatic ring, either of which may be substituted with one or more functional groups, or else R2 represents an alkyl group, which may be straight or branched, and which may be substituted with one or more functional groups;
R3 and R4 each independently represent hydrogen, or else R3 and R4 form members of a common cycloalkyl or aromatic ring, either of which may be substituted with one or more functional groups, or else one or both may represent a branched or unbranched, saturated or unsaturated aliphatic or alkyl-substituted cycloalkyl hydrocarbon radical; or else each represents an aryl hydrocarbon radical, or an alkylaryl hydrocarbon radical, either of which may be substituted with one or more functional groups.
One skilled in the art would expect a broad range of products from these reactions, and difficulty in stopping the reactions at the β-hydroxy-ketone stage. The further condensation of the α-β unsaturated ketones with the ketone of Formula II, or with the aldehyde of Formula I, or with other ketonic and aldehydic species, leads to a plethora of by-products and can represent significant yield losses as well as necessitating complicated and expensive purification schemes for the commercial production of high purity β-hydroxy-ketones and/or α,β-unsaturated ketones. For example, in the preparation of 2-heptanone via the condensation of n-butyraldehyde with acetone, the self-condensation of n-butyraldehyde to form 2-ethyl-2-hexenal is a particularly troublesome by-product. Its hydrogenated form; 2-ethylhexanal, boils less than 10° C. apart from 2-heptanone, and is therefore difficult to separate economically from 2-heptanone by distillation.
Generally, the equilibrium constant for ketone-ketone self-condensation is small, and products from this pathway are of lesser importance. One particular exception is when the ketone is acetone. Formation of the self-condensation products 4-hydroxy-4-methyl-2-pentanone and 4-methyl-3-penten-2-one can be appreciable under certain reaction conditions.
When the aldehyde of Formula I possesses no hydrogen alpha to the carbonyl, then the aldehyde-aldehyde self-condensation pathway cannot occur. However, under strongly basic conditions, the Cannizzaro reaction (in which two aldehyde groups are transformed into the corresponding alcohol and carboxylic acid salt) is known to be favorable and can represent significant yield losses of aldehyde, as well as consume a stoichiometric amount of base. T. A. Geissman, in Chapter 3 of Organic Reactions, Vol. 2, R. Adams, editor, 1944, pp 94-113, teaches a commonly employed procedure in which the aldehyde is shaken or stirred with strong (i.e., 50 weight percent) aqueous or alcoholic alkali metal hydroxides or alkoxides to effect the Cannizzaro reaction in good to excellent yields. Thus, one skilled in the art would expect the Cannizzaro reaction to occur, with consumption of the small amounts of base and subsequent termination of the reaction, using the process disclosed in the instant invention, as further discussed below.
Many methods have been disclosed in the art to perform crossed aldol condensation reactions. Such methods can be divided roughly into four general categories: 1) two-phase liquid reactions using dilute aqueous base as the catalyst, generally a hydroxide of an alkali- or alkali-earth metal; 2) base-catalyzed liquid phase reactions (may or may not be multiple liquid phases) with a compatibilizing agent, a solubilizing agent, or a phase transfer agent present (hereinafter sometimes referred to as a solubilizing agent), for example, an alkanol, a polyol, or a polyether alcohol, generally catalyzed by an alkoxide or hydroxide of an alkali- or alkali-earth metal; 3) amine-catalyzed condensation reactions; and 4) heterogeneous catalysis with a metal or metal oxide on a solid support. The latter method is often done in the gas phase, and the catalyst may combine further reaction functionality, i.e., hydrogenation.
The category comprising two-phase liquid reactions using dilute aqueous base as the catalyst, in the absence of a solubilizing agent, is exemplified in the following.
U.S. Pat. No. 6,232,506 discloses a process for producing 6-methyl-3-hepten-2-one, and its analogues, by the crossed aldol condensation of acetone with 3-methyl-butanal (isovaleraldehyde), catalyzed by an alkali metal or alkali earth metal hydroxide as catalyst. The catalyst is provided as a 0.5 to 30 weight percent, preferably 1 to 10 weight percent, aqueous solution, at a caustic-aldehyde molar ratio of 0.001 to 0.2. The process is carried out in semi-batch mode, with separate continuous feeds of aldehyde and dilute caustic to a stirred reaction zone initially comprising acetone. In Example 1 of the patent, using the preferred 2 wt. % aqueous caustic catalyst solution, the reaction mixture forms distinct aqueous and organic phases, with water being present in an amount of about 39 wt. %, based on the total weight of the reactant mixture Cited yields are typically about 66% to 6-methyl-3-hepten-2-one and 3.3% 6-methyl-4-hydroxy-heptan-2-one.
U.S. Pat. No. 5,840,992 ('992) teaches a process for producing 6-methylheptan-2-one by the crossed condensation of acetone with 3-methyl-butanal, in the presence of an aqueous alkali or alkali earth metal hydroxide as catalyst, at a catalyst-aldehyde molar ratio of 0.001 to 0.20. The resulting β-hydroxy ketone condensation product is further subjected to reduction under dehydrating conditions to produce 6-methylheptan-2-one. The process according to the '992 patent may be carried out continuously in plug flow or batch-wise mode. Typical molar selectivities on 3-methyl-butanal are about 75 to 80 percent, with the best results being achieved in the batch mode of operation. Although the '992 patent discloses that the basic catalyst substance may be used as an aqueous solution at a concentration between 1 and 50 percent, the process is reduced to practice only with a catalyst concentration of 5 weight percent aqueous sodium or potassium hydroxide. The authors of the '992 patent clearly fail to contemplate the advantages of using concentrated hydroxides or alkoxides of alkali earth- or alkali-metals as catalysts, for example at greater than 15 or 20 weight percent, while controlling the absolute amount of water present in the reaction mixture, as exemplified in the instant invention. Thus, the process disclosed in the '992 patent achieves only modest yields.
U.S. Pat. Publ. No. 2002/0161264 (the '264 publication) discloses a process for the preparation of α,β-unsaturated ketones by the crossed condensation of an aldehyde with a ketone. The condensation reaction described can be carried out in a tubular reactor as a multiphase liquid reaction in which a dilute aqueous caustic catalyst (0.1 to 15 weight percent caustic, preferably 0.1 to 5 weight percent) is the continuous phase and the aldehyde/ketone reactants are the dispersed phase. The disclosure of the '264 document explains that the reaction must be conducted with separate catalyst and reactant phases, and that the mass ratio of the aqueous caustic phase to the organic reactant phase can be from 2:1 to 10:1, preferably even greater. The reference clearly fails to contemplate the advantages of a high caustic catalyst phase reaction in which the amount of water present is kept relatively low.
U.S. Pat. No. 6,433,230 (the '230 patent) discloses a process similar to that described in the '264 publication, being a base-catalyzed aldol condensation that includes reacting the aldehydes and/or ketones with an aqueous catalyst solution under adiabatic reaction conditions, and thereafter separating the resulting reaction mixture. The condensation can be carried out in at least one stirred vessel or at least one tubular reactor, in which a dilute aqueous caustic catalyst (0.1 to 10 weight percent caustic, preferably 0.1 to 3 weight percent) constitutes one phase and the aldehyde/ketone reactants constitute another phase. Weight ratios of the organic reactant phase to the aqueous caustic phase of from 1:2 to 1:10, or preferably greater, are said to be useful. A cited advantage of the process is that, because of the adiabatic reaction conditions, the heat of reaction remains in the reaction mixture, assisting the subsequent rapid distillation of the top product, water and unreacted starting material. However, the reference clearly fails to contemplate the advantages of a high caustic catalyst phase reaction in which the amount of water present is kept relatively low.
A process similar to that disclosed in the '264 publication is disclosed in U.S. Pat. Publ. No.2002/0128517, a process for the preparation of 6-methylheptan-2-one and corresponding homologous β-branched methylketones, in particular phytone and trathydrogeranyl acetone, by the two-liquid phase crossed condensation of acetone with 3-methyl-butanal, prenal or the like, in the presence of both a dilute aqueous alkali or alkali earth metal hydroxide catalyst for the aldol step and a noble metal catalyst for hydrogenation. A base concentration of 0.01 to 20 weight percent in the aqueous catalyst phase is said to be useful, from 0.5 to 5 wt. % being preferred, though the concentration is said not to be critical. The processes exemplified in this document use relatively low concentrations of caustic with a relatively high amount of water, with respect to the total weight of the reactants. The reactivity toward self-condensation of the hindered, branched aldehyde, 3-methyl-butanal, is low, resulting in molar selectivities based on the aldehyde around 93-95 mole percent.
Kyrides, Journal of the Amer. Chem. Soc., Vol. 55, August, 1933, pp. 3431-3435, teaches a process for the crossed condensation of acetaldehyde or n-butanal with 2-butanone to produce the corresponding β-hydroxy ketone. The aldehyde is added semi-batchwise to a stirred reaction zone containing an excess of ketone and a small amount of 10 weight percent aqueous sodium hydroxide as catalyst. Typical conditions cited are temperatures less than 20° C. in the reaction zone, more typically less than 10° C., with a molar ratio of ketone to aldehyde between 7 and 8, and molar ratio of caustic to aldehyde between 0.0085 to 0.03. At these low temperatures, the solubility of the caustic in the reaction mixture is quite low and tends to separate into a distinct catalyst-containing liquid phase. The disclosed processes are characterized by long batch reaction times and poor space-time yields, and would require expensive refrigeration on a commercial scale to maintain temperatures less than 20° C. in the reaction zone. The processes give only modest molar yields on the aldehyde to the β-hydroxy ketones of about 70-85%.
Grignared and Dubien, Ann. Chim., Vol. 2, 1924, pp.282-290, teach a process for the crossed condensation of acetone with n-butyraldehyde to produce 4-hydroxy-2-heptanone. The aldehyde is added semi-batchwise to a stirred reaction zone containing an excess of ketone and a large amount of 12-15 weight percent aqueous sodium hydroxide as catalyst. Conditions cited are temperatures less than 20° C. in the reaction zone, preferably between 15° and 20° C., with a molar ratio of acetone to n-butyraldehyde of 2.5, and molar ratio of caustic to aldehyde of 0.31. Although the caustic concentration used is moderate, the amount of water thereby introduced, with respect to the total weight of reactants, is relatively high, so that the process is less advantageous than that according to the present invention. Further, at the low temperatures cited, the solubility of the caustic in the reaction mixture is quite low and tends to separate into a distinct catalyst-containing liquid phase. The process as disclosed requires long batch reaction times (six hours), provides poor space-time yields, would require expensive refrigeration on a commercial scale to maintain temperatures less than 20° C. in the reaction zone, and gives only modest molar yields on the aldehyde to the β-hydroxy ketone of about 80%.
U.S. Pat. No. 2,200,216 teaches a two stage batch reaction process for the production of high-molecular weight unsaturated ketones. The first step involves a crossed condensation of aldehydes containing from 4 to 8 carbon atoms with ketones containing from 3 to 5 carbon atoms in the presence of an alkaline earth hydroxide (15 weight percent aqueous barium hydroxide) to produce unsaturated ketones. After isolation, the unsaturated ketone products are then subjected to a second self-aldol reaction step in the presence of dilute alkali alkoxide in the corresponding alcohol. The concentration of alkaline earth hydroxide used is moderate, the amount of water thereby introduced into the reaction mixture (with respect to the total weight of the reactants) being relatively high. The disclosed multi-step process is fairly complicated, requires expensive reagents, and gives modest yields, typically about 70 percent per step.
U.S. Pat. No. 6,288,288 to Springer discloses a process for preparing saturated alcohols comprising effecting an aldol condensation of alkyl methyl ketones of 6 to 8 carbon atoms which are branched at the β-carbon atom, with aldehydes of 4 to 15 carbon atoms which are branched at the α-carbon atom, to form α,β-unsaturated ketones, with subsequent hydrogenation of the α,β-unsaturated ketones to obtain alcohols, wherein the aldol condensation is carried out at a temperature of 60 to 130° C. in the presence of a 30-55 weight percent aqueous solution of an alkali metal hydroxide.
Only the aldol condensations of 4-methyl-2-pentanone with 2-ethylhexanal and 4-methyl-2-pentanone with 2-methyl-butanal are disclosed in this document. The preferred caustic to aldehyde molar ratio is said to be from 0.15 to 1.0, with the best yields (typically 73 to 84 mole percent) achieved above a ratio of 0.35. Thus, very large amounts of caustic are required. Such a high caustic loading is not miscible in the organic reactants, and as a result, the process operates with two distinct liquid phases present in the reaction zone, as confirmed by the teaching that the aqueous catalyst phase can be decanted away from the organic product phase at the end of the reaction. In the preferred embodiment of this patent, the reactants are added slowly over several hours to a batch reaction zone, and the water generated by the dehydration of the initially formed β-hydroxy ketone is removed continuously. Although the concentration of the aqueous solution of an alkali metal hydroxide used is relatively high, the disclosed processes also use a relatively high amount of water, with respect to the total weight of the reactant mixtures. The process disclosed thus requires excessive levels of concentrated caustic catalyst, demonstrates poor reactor productivity, modest selectivity, and requires complicated water removal during the reaction.
A number of patents and references in the open literature are directed toward base-catalyzed, liquid phase aldol condensation reactions with a compatibilizing agent, a solubilizing agent, or a phase transfer agent present. U.S. Pat. Nos. 2,088,015 ('015), 2,0880,016 ('016), 2,0880,017 ('017), and 2,088,018 ('018) disclose related processes for the preparation of higher ketones in which the reactions are conducted in the presence of dilute alkali metal alkoxides in large amounts of the corresponding alcohol as solubilizing agent, typically 5-10 weight percent alkali metal hydroxide or alkoxide in methanol. Disclosed ketones include undecyl ketones ('015), nondecyl ketones ('016), ketones derived from 2-ethylbutyraldehyde and methyl alkyl ketones ('017), and C10 or greater ketones derived from 2-ethylbutyraldehyde and methyl alkyl ketones ('018). Temperature in the reaction zone is relatively low, with reaction times often longer than 10 hours. The reaction media is neutralized with dilute acid, filtered to remove salts, distilled, and hydrogenated to give saturated ketones. Several years prior to issuance of these patents, Powell, Journ. Amer. Chem. Soc., Vol. 46, 1924, pp. 2514-2517, laid out a similar process for the condensation of n-butyraldehyde with 2-butanone in the presence of alcoholic potassium hydroxide. Disadvantages for commercial application of these processes include the low temperature of operation, long reaction times, expensive alkoxide reagents, and the difficult recovery of product, complicated by the presence of the alcohol solvent.
U.S. Pat. No. 4,956,505 discloses a process for the condensation of pinacolone and p-chlorobenzaldehyde, in an alcohol as solvent, to give 4,4-dimethyl-1-(p-chlorophenyl)3-penten-2-one, with subsequent hydrogenation to 4,4-dimethyl-1-(p-chlorophenyl)pentan-2-one. The condensation is catalyzed with 5-30, preferably 10-15 equivalents of alkali metal hydroxide base dissolved in C1 to C3 monohydric or polyhydric alcohols. The preferred solvent is methanol; particularly preferred is an amount of 20-40 weight percent of the reaction mixture. Although yields are reasonable, typically about 90% based on p-chlorobenzaldehyde, the reactions are slow and require expensive and complicated recycle of the solubilizing alcohol.
Several patents disclose the use of polymeric or oligomeric ethylene glycols or polyhydric alcohols, as phase transfer catalysts or solvents, in combination with dilute alkali metal hydroxide catalysts. U.S. Pat. No. 5,055,621 teaches the use of alkali metal hydroxide dissolved in a glycol, preferably diethylene glycol, optionally with water, for the condensation of benzaldehyde with straight-chain aldehydes to produce α-cinnamic aldehydes. U.S. Pat. No. 5,663,452 describes the aldol condensation of n-butyraldehyde in the presence of an alkali or alkali earth metal hydroxide dissolved in polyethylene glycol phase transfer catalyst. U.S. Pat. Publ. No.2002/0058846 teaches a process for the preparation of 6-methylheptan-2-one and corresponding homologous β-branched methylketones, in particular phytone and trathydrogeranyl acetone, by the two-liquid phase crossed condensation of acetone with 3-methyl-butanal, prenal or the like, in the presence of a dilute aqueous alkali or alkali earth metal hydroxide catalyst dissolved in a polyhydric alcohol for the aldol step, and a noble metal catalyst for hydrogenation. The polyhdric alcohol is preferably glycerol. All of these processes suffer from low reaction rates and complicated separation schemes for recovery and recycling of the phase transfer catalyst.
The category of amine-catalyzed condensation reactions includes U.S. Pat. Nos. 5,583,263 and 5,300,654. The category of heterogeneous catalysis with a metal or oxide on a solid support is exemplified by U.S. Pat. Nos. 5,936,131, 6,271,171, and 4,739,122.
A number of patents are directed solely to catalysts used to improve the selectivities and yields of aldol condensations. U.S. Pat. No. 4,146,581 to Nissen, et. al. describes a catalyst system for producing higher ketones; U.S. Pat. No. 4,270,006 to Heilen, et al. describes a catalyst system largely incorporating noble metals and salts of rare earth metals; U.S. Pat. No. 4,701,562 to Olson teaches a process for condensing aldehydes catalyzed by a nonzeolitic aluminophosphate; and U.S. Pat. No. 4,049,571 to Nissen, et. al. describes another catalyst for one-step aldol condensations that yield higher ketones.
Several authors have disclosed processes for crossed aldol condensations catalyzed by high levels of caustic. Weizmann and Garrard, J. Chem. Soc, Pt. 1, Vol. 117, 1920, pp. 324-338, prepared 3-hepten-2-one by the batch-wise crossed condensation of n-butyraldehyde and acetone catalyzed with solid sodium hydroxide. In their process, the aldehyde was fed in excess (ketone/aldehyde molar ratio of 0.96), with 0.055 equivalents of base per mole of aldehyde. No temperature control was attempted, the reaction times were 12 hours, and typical yields were about 30-35% based on n-butyraldehyde, with large quantities of the n-butyraldehyde self-condensation product, 2-ethyl-2-hexenal, observed.
Eccott and Linstead, J. Chem. Soc, Pt. 1, Vol.133, 1930, pp. 904-911, prepared a mixture of 4-hydroxy-2-heptanone and 3-hepten-2-one by the low-temperature, (5-10° C.) batch-wise crossed condensation of n-butyraldehyde and acetone catalyzed by 50 weight percent sodium hydroxide. In their process, the acetone was fed in excess (ketone/aldehyde molar ratio of 3.0), with 0.50 equivalents of base per mole of aldehyde. The high caustic to aldehyde loading and long reaction times resulted in typical yields of about 30% based on n-butyraldehyde. These authors failed to recognize the utility of catalyzing aldol condensation reactions with small amounts of concentrated alkali metal hydroxides providing relatively low amounts of water in the reaction mixture, with respect to the total weight of the reactants, nor did they recognize the proper reaction parameters, such as contacting mode, time, temperature, and concentrations, for optimizing conversion and selectivity.
There remains a need in the art for an aldol condensation process characterized by high yield and selectivity for β-hydroxy ketones and α,β-unsaturated ketones, that can be used over a wide range of temperatures, and that has relatively short reaction times.